We read with interest the report on postulated atorvastatin
induced lactic acidosis [1]. In our view, the arguments outlined by its
authors do not support this hypothesis at all, for the reasons outlined
below:
a) The patient clearly had a mixed acid-base disturbance (combined
respiratory alkalosis and metabolic acidosis, as evidenced by the normal
pH of 7.39 coupled with severe hypocapnia)....
We read with interest the report on postulated atorvastatin
induced lactic acidosis [1]. In our view, the arguments outlined by its
authors do not support this hypothesis at all, for the reasons outlined
below:
a) The patient clearly had a mixed acid-base disturbance (combined
respiratory alkalosis and metabolic acidosis, as evidenced by the normal
pH of 7.39 coupled with severe hypocapnia).
b) Both the delta anion gap (24.2 –16= 8 mEq/L) and the decrease in
standard base excess (which we use in preference to whole blood base
excess and calculate to be -17.9 mEq/L) are much larger than the delta
lactate, which is only approximately 1.5 mmol/L. This clearly indicates
that the metabolic acidosis is multifactorial, and that another
pathological process rather than hyperlactaemia is the major contributor
to the raised anion gap. This should lead to a search for other causes of
a raised anion gap. For example, one would need to measure serum
salicylates, the osmolar gap and plasma beta-hydroxybutyrate. With
concerns of statin myopathy, a serum CK would be useful. With a history of
paracetamol ingestion, pyroglutamic acidosis is a likely possibility and
could be diagnosed using a urinary organic acid screen [2].
c) The authors’ discussion of potential causes of an elevated plasma
lactate concentration is incomplete. For example, they have failed to
discuss the possible contribution of salbutamol to the hyperlactaemia.
Furthermore, covert tissue hypoxia is a possibility despite normal
arterial oxygenation, which can lead to hyperlactaemia.
d) If it were to be a mitochondrial paralysis from statin therapy, it
is hard to imagine an immediate clinical improvement upon cessation of the
medication.
Other significant and fundamental errors in the report detract from
its validity. They include the following:
a) The [HCO3-] is said to be 13.8 mmol/L, whereas at the quoted pH (7.39)
and PCO2 (1.2 kPa) it would be much lower at 5.3 mmol/L.
b) The quoted PO2 of 19.3 kPa on room air implies a negative A-a gradient
of nearly 1 kPa. This is clearly impossible in any patient, let alone an
82 year old woman. Presumably supplemental oxygen was being administered.
c) The mention of unmeasured cations instead of anions in the abstract when
discussing a raised anion gap is a cause for confusion.
We recognise that simvastatin has been reported to induce lactic
acidosis through mitochondrial failure [3]. However, this report describes
a mixed acid-base disorder not primarily due to lactate. Hence, the
authors cannot claim that it adds to the body of evidence supporting the
link between statin therapy and lactic acidosis.
(2) Dempsey GA, Lyall HJ, Corke CF, Scheinkestel CD. Pyroglutamic acidemia:
a cause of high anion gap metabolic acidosis. Crit Care Med
2000;28(6):1803-7.
(3) Goli AK, Goli SA, Byrd RP, Jr., Roy TM. Simvastatin-induced lactic
acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002;72(4):461-4.
In his letter of the letter 18th August 2004, Dr Chandler makes some
interesting comments on our paper “Increased neutrophil apoptosis in
chronic fatigue syndrome” [1]. He states that “a more likely explanation
for the group's findings are that CFS patients have a primary
psychological disorder with the secondary expected immune dysfunction”. We
strongly disagree with this statement.
In his letter of the letter 18th August 2004, Dr Chandler makes some
interesting comments on our paper “Increased neutrophil apoptosis in
chronic fatigue syndrome” [1]. He states that “a more likely explanation
for the group's findings are that CFS patients have a primary
psychological disorder with the secondary expected immune dysfunction”. We
strongly disagree with this statement.
It is noteworthy that many research findings that support a physical
basis to CFS are constantly under attack and are commonly reduced to the
lowest common denominator i.e. that CFS is “psychological in origin”. Dr
Chandler comments that, “there is a wealth of data suggesting that primary
depressive illnesses are associated with immune function defects”. That
may be true, however, we are not aware of a study which shows that
neutrophils are significantly apoptotic in depressed patients and that
this is associated with an increase in the pro-inflammatory cytokine,
transforming growth factor â-1. Furthermore, the CFS patients in our study
were not depressed or excessively anxious and we have already reported on
their psychological status in a separate report [2]. Indeed, three groups
of CFS patients are mentioned in that report [2]: those with self-reported
symptoms which developed sporadically (CFS, n =48); after Gulf War service
(GW, n =24); and following exposure to organophosphate insecticides (OP, n
=25). All of these patients underwent a clinical examination which
included psychiatric status, they all completed the MOS SF-36 quality of
life and Hospital Anxiety and Depression scales, and fulfilled major and
minor criteria for CDC-1994 CFS. The GW and OP cohorts had significant
impairments to both emotional and mental health measures (GW > OP) when
compared to their own controls and to the sporadic CFS patients. We have
not yet reported on the neutrophil apoptosis data on the GW and OP
patients (or in other studies of their lymphocyte function) but neither
cohort had any difference in the percentage of neutrophils undergoing
apoptosis when compared with their respective controls. We additionally
found that the GW and OP cohorts had no difference in the percentages of
tumour necrosis factor receptor-1 death receptor molecules expressed on
their neutrophils or levels of platelet poor plasma activated transforming
growth factor â-1. This data is at variance with Dr Chandlers comment that
“a more likely explanation for the group's findings are that CFS patients
have a primary psychological disorder”.
What is clear is that the term CFS is heterogeneous and lacks
specificity as others have reported [3, 4]. The CFS patients in our study
should more accurately be described as those having myalgic
encephalomyelitis (ME) as defined by Ramsay [5] which has recently been
reported to be operationally distinct from those with chronic fatigue and
chronic fatigue syndrome [6] especially in the neurological and
neuropsychiatric areas reported in our recent study [2]. Fatigue is a
symptom and not a disease and, ultimately, “an operational CFS case
definition will need to be based on empirical studies designed to
delineate the possibly distinct biological pathways that result in
illness” [3]: such a case definition already exists [7]. Our paper on
increased neutrophil apoptosis in a specific subset of patients within the
CFS construct goes some way to assisting in this process of
classification.
References
(1) Kennedy G, Spence V, Underwood C. Increased neutrophil apoptosis
in chronic fatigue syndrome. J Clinical Pathology 2004; 57: 891-3
(2) Kennedy G, Abbot NC, Spence V, Underwood C, Belch JJF. The
specificity of the CDC-1994 criteria for chronic fatigue syndrome: a
comparison of health status in three groups of patients who fulfill the
criteria. Annals of Epidemiology 2004; 14: 95-100
(3) Reeves WC, Lloyd A, Vernon SD et al. Identification of
ambiguities in the 1994 chronic fatigue syndrome research case definition
and recommendations for resolution. BMC Health Services Research 2003,
3:25
(4) Jason LA, King CP, Richman JA, et al. US case definition of
Chronic Fatigue Syndrome: Diagnostic and theoretical issues. J Chronic
Fatigue Syndrome 1999; 5: 3–33.
(5) Ramsay, M. A. (1988). Myalgic encephalomyelitis and post-viral
fatigue states: The saga of Royal Free disease (2nd ed.). Hampshire, UK:
Gower.
(6) Jason LA, Helgerson J, Torres-Harding SR et al. Variability in
diagnostic criteria for chronic fatigue syndrome may result in substantial
differences in patterns of symptoms and disability. Evaluation & the
Health Professions 2003; 26: 3-22
(7) Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG,
Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome:
Clinical working case definition, diagnostic and treatment protocols. J
Chronic Fatigue Syndrome 2003; 11: 7–116.
I welcome the latest research on neutrophil
apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite
the concerns raised, by hundreds of well educated people, involved with
M.E. worldwide, for many years, someone who ha...
I welcome the latest research on neutrophil
apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite
the concerns raised, by hundreds of well educated people, involved with
M.E. worldwide, for many years, someone who has admitted to being "quite
new" to a SHO post, on a Chronic Fatigue ward, has assumed, that he has
the authority and education, to criticise the outcome of this research, at
this stage, when most people admit they are not 100% sure about the
aetiology M.E.
This seems to be a pre-determined blinkered
attitude, that screams out "l know all there is to know". I will not tolerate,
on behalf of the members of the M.E.Association, the approach
perpetrated by information solely provided by the Psychiatrists, who have
continually reported, that M.E. is an illness belief, that one has a real
illness that must not be encouraged, by validating, or providing medical
testing, for a non-illness.
The Department of Health have on many occasions, declared
that they are duty bound, to take account of all national and international
information and evidence, from all sources so as to provide as broad a spectrum of ideas and treatment plans as
is reasonable. And to provide the least damaging and most helpful, practical
treatment or advice for all. The Canadian Guidelines have the potential to be adapted for world
wide use, but l have been told the government appears to use international advice only, when it suits
them, and ignore it when it suits patients.
Has the DOH considered fully, the possible financial implications,
for us all, if there is no research into the physical, epidemiological and
biological cause of M.E.?
This has resulted in many cases of long term physical damage,<see 25%
Report 2002-2004> which has resulted in the death of hundreds of people
every year.
A high proportion are those have been young adults, who have been
constantly, denied referrals, to the independent, M.E. specialists that we
have in our files.
It is disappointing to read Ian Chandler's comments on this work. Dr
Chandler's rather simplified logic seems to work like this:
- Depression is a psychiatric illness.
- Immunological abnormalities can be found in depression.
- CFS is also a psychiatric disorder and so there is no point in
measuring immunological parameters because any findings will be redundant.
CFS remains a debilitating condition for which more pathological data
is desperately needed. Psychiatric studies, whilst having been of value in
the past, are failing to provide new insight into disease aetiology, nor
are they providing effective treatments, particularly for those patients
who are most seriously affected by the condition.
Immunological profiling will undoubtedly lead to immunomodulatory
interventions for a number of medical conditions. Perhaps one of these
will be CFS, perhaps not. It may even be the case for certain subgroups
with clinical depression. The point is, we'll never know unless we
encourage this type of research.
I hope that medical professionals like Dr Chandler are prepared to
adjust their views on CFS if and when further findings are published.
Ian Chandler's response to this study, insisting that any immune
abnormality is secondary to depression is without scientific merit.
Several studies comparing ME/CFIDS patients with patients suffering
from clinical depression have found important physical differences. SPECT
brain imaging studies sh...
Ian Chandler's response to this study, insisting that any immune
abnormality is secondary to depression is without scientific merit.
Several studies comparing ME/CFIDS patients with patients suffering
from clinical depression have found important physical differences. SPECT
brain imaging studies show ME/CFIDS patients suffer from hypoperfusion
that gets worse, rather than better, after exercise, a pattern not found
in depressed patients.
Studies have also show a reduced pain threshold in ME/CFIDS patients,
which again responds to exercise in a manner opposite to that found in
healthy and depressed control groups - pain thresholds get lower, instead
of higher.
These studies amount to clinical confirmation of a simple but often-
ignored distinction. When people suffering from depression exercise they
feel better, when people suffering from ME/CFIDS exercise they feel much
worse, often for days afterwards.
As an adult male diagnosed with ME/CFIDS, I can tell you that few
things are more 'depressing' than encountering medical professionals like
Mr. Chandler, who discount all evidence of organic illness in ME/CFIDS
patients because of a willful, even perverse attachment to the belief that
our symptoms are 'all in our heads'.
To hold to that position despite all evidence to the contrary
demonstrates a mindset in which empathy and scientific curiosity are
markedly absent - in other words, a mindset uniquely unsuited for
responsible diagnosis and treatment of complex illnesses like this one.
Mr. Chandler's position is one which cannot be altered by encounters
with contrary facts. If presented with undisputable evidence of, say,
chronic bacterial infection in a patient with ME/CFIDS, Mr. Chandler will
acknowledge the infection but deny that it has anything at all to do with
ME/CFIDS itself.
Do depressed people experience symptom remission when treated with
Ampligen, an immune-modulating drug? Do depressed people regain their
health and vitality after long-courses of antibiotics? The answer, of
course, is no. Patients with ME/CFIDS, however, do.
Mr. Chandler would no doubt object that the studies demonstrating
this improvement are not large enough to be considered definitive. The
point, of course, is that views such as his are the primary reason that
adequate research budgets for these illnesses are not forthcoming.
Having read Kennedy et al's short report on finding increased neutrophil apoptosis in patients with chronic fatigue syndrome, I am
unable to agree with their conclusion that "these findings provide new
evidence that patients with CFS have an underlying abnormality in their
immune cells" [1]. They provide no evidence that the immune defect is
causative, and, on the contrary, there is a wealth of...
Having read Kennedy et al's short report on finding increased neutrophil apoptosis in patients with chronic fatigue syndrome, I am
unable to agree with their conclusion that "these findings provide new
evidence that patients with CFS have an underlying abnormality in their
immune cells" [1]. They provide no evidence that the immune defect is
causative, and, on the contrary, there is a wealth of data suggesting that
primary depressive illnesses are associated with immune function defects.
Research papers in neuropsychology journals over the last year have
described abnormalities of natural killer cell function, T cell function,
and neutrophil function in psychological stress, depression, and
associated loneliness [2-5]. As somebody who has spent an albeit
relatively short time working as an SHO in a CFS specialist ward, I would
suggest that a more likely explanation for the group's findings are that
CFS patients have a primary psychological disorder with the secondary
expected immune dysfunction predicted by the referenced papers above.
References
(1) Kennedy G, Spence V, Underwood C. Increased neutrophil apoptosis
in chronic fatigue syndrome. J Clin Pathol 2004;57:891-3.
(2) Frank MG, Hendricks SE, Burke WJ et al. Clinical response
augments NK cell activity independent of treatment modality. Psychol Med
2004 Apr; 34(3)491-8.
(3) Steptoe S, Owen N, Kunz-Ebrecht SR et al. Loneliness and
neuroendocrine, cardiovascular and inflammatory stress response in middle-
aged men and women. Psychoneuroendocrinology 2004 Jun 29(5)593-611.
(4) Silberman DM, Ayelli-Edgar V, Zorilla-Zubilete M et al. Impaired
T cell dependent humoral response and its relationship with T lymphocyte
sensitivity to stress hormones in a chronic mild stress model of
depression. Brain Behav Immuno 2004 Jan 18(1)81-90.
(5) Irie M, Asami S, Ikeda M et al. Depressive state relates to
female oxidative DNA damage via neutrophil activation. Biochem Biophys Res
Commun 2003 Nov 28;311(4)1014-18.
Recently, we read with the interest the paper Lack of
lymphangiogenesis during breast carcinogenesis from Vleugel et al. (J Clin
Pathol.2004; 57: 746-751) [1]. These authors investigated the role of lymphangiogenesis in breast carcinogenesis. Whist the resident lymphatics
and/or new tumour-induced lymphatic vessels are collapsed by the intra-
tumoral pressure, or if they do facilitate the neopl...
Recently, we read with the interest the paper Lack of
lymphangiogenesis during breast carcinogenesis from Vleugel et al. (J Clin
Pathol.2004; 57: 746-751) [1]. These authors investigated the role of lymphangiogenesis in breast carcinogenesis. Whist the resident lymphatics
and/or new tumour-induced lymphatic vessels are collapsed by the intra-
tumoral pressure, or if they do facilitate the neoplastic spread are
crucial questions to the understanding the biological behaviour of cancer
metastasis pathways and to elaborate therapeutics targets for the new
generation of chemotherapies [2].
Padera et al. demonstrated that the
mass of malignant cells are able to compress the intra-tumoral lymphatic
vessels [3]. These authors have hypothesised that the tumoral compression harm
the lymphatic activity in intra-tumoral field, deforming and inducing
damages in the lymphatic structures what seriously limits the
identification of lymphatics.
The paper of Vleugel et al. [1]
investigated two alleged hypothesis that closely embrace the intra-tumour
absence of lymphatics: the collapse of lymphatic vessels or the lack of
lymphangiogenesis in breast cancer. These authors used LYVE-1 to
discriminate lymphatic vessels due to its presumed specificity to
recognize lymphatics, and CD31 for the blood vessels. LYVE-1, a hyaluronan
receptor expressed during the lymphatic vessels development is not
exclusively expressed by lymphatics. However, in spite of conflicting
results, LYVE-1 is considered a classical marker of lymphatic vessels [2].
Vleugel et al. [1] showed that both blood vessel density (BVD) and lymph
vessel density (LVD) were similar among the normal and non-neoplastic
proliferative (hyperplastic) breast tissue. Additionally, ductal carcinoma
in situ (DCIS) has demonstrated increased BVD but not LVD. As mentioned
by the authors, this is an important point to be considered, in view of
the fact that no significant increased pressure is expected in DCIS. The
authors also found an inverse correlation between LVD and the size of
DCIS, probably due to the replacement of the stroma by the neoplastic
cells. This progressive absence of lymph vessels seems to be the reason of
the lacking of lymphangiogenesis in breast cancer. In most of breast
invasive carcinomas studied, lymphatic vessels were not demonstrated,
suggesting that the complete destructive growth pattern in invasive
carcinoma induce the formation of a new stroma without lymphatics that
replace the original destroyed stroma.
Recently, we studied lymphangiogenesis in a series of in situ and invasive ductal carcinomas,
using VEGFR 3 as a marker. In accordance with the results reported by
Vleugel et al.[1] we also did not observed increasing of lymphatic vessels
surrounding ducts involved by DCIS. In invasive carcinomas we observed
mainly at periphery of the tumour some small distorted vessels faintly
decorated by VEGFR 3. We did not find any relationship between the number
of lymphatic vessels and some clinical-pathological parameters of
aggressiveness in breast cancer such as: tumour size, grading and presence
of lymph node metastasis. These findings reinforce the idea that
lymphangiogenesis can not be important for breast carcinogenesis and also
for breast cancer progression. In spite of experimental models had
demonstrated that lymphangiogenesis can promote metastasis, this is not so
evident in human tumours. The tangible evidences seriously indicate that
the breast cancer spread do not depends on the intra-tumoral lymphatic
vessels, but maybe via pre-existing lymphatics [4,5]. Moreover, new
insights suggesting the existence of a potential interaction between the
tumour and the lymphatic vessels promoted by Hyaluronan expression
introducing novel likely mechanisms to the metastatic spread by the
lymphatics6. Another important point raised in our study was the role of
VEGFR-3 in lymphangiogenesis. In our cases we also detected VEGFR-3
expression in some intra-tumoural blood vessels. Recently, Scavelli et al.
[6] call the attention for the cross-talking between blood and lymphatic
vessels in neoplastic conditions. Understandingly, the blood vessels
marked by the VEGFR-3 can expose the pivotal action of VEGFR-3 in
angiogenesis during the development, in same way reproducible under
carcinogenesis scenario. However, one of the most outstanding findings in
our study was the detection of VEGFR-3 expression in breast myoepithelial
cells. Although expression of VEGFR-1 and VEGFR-2 had been previously
described in epithelial cells, including breast malignant cells [7], as
far as we know it is the first time that VEGFR-3 expression was described
in breast myoepithelial cells.
In conclusion, the paper published by Vleugel et al. [1] provides new and
exciting evidences of the role of new vasculature, lymphatic and blood
vessels, in the breast carcinogenesis. Provide also arguments to be
explored concerning the relation of molecular expression of LYVE-1 and
other related-lymphangiogenic markers in lymphatic tumour-related vessels
during the metastatic spread. Comprehensive studies with lymphatic markers
are still required to address the mechanism of tumour behaviour and
metastatic potential. The model explored by the authors should be
reproduced using other markers for lymphatics and in other tumours to
confirm if the lack of lymphangiogenesis in breast carcinogenesis can be
extrapolate or not to others malignancies.
Adhemar Longatto Filho, PhD, PMIAC;
Life and Health Science Research Institute, School of Health Sciences,
University of Minho, Braga, Portugal
Fernando C. Schmitt, M.D., PhD, MIAC.
IPATIMUP and Medical Faculty, Porto University, Porto, Portugal
e-mail: fernando.schmitt@ipatimup.pt
Address for correspondence:
Fernando C. Schmitt, M.D., Ph.D, M.I.A.C.
IPATIMUP
Rua Roberto Frias s/n
4200 Porto
Portugal
Phone: 351 22 557 0700
FAX: 351 22 557 0799
e-mail: fschmitt@ipatimup.pt
Adhemar Longatto Filho is currently postdoctoral fellowship at
University of Minho, supported by a FCT grant (SFRH/BPD/14616/2003)
References
(1) Vleugel MM, Bos R, van der Groep P, et al. Lack of
lymphangiogenesis during breast carcinogenesis. J Clin Pathol.2004; 57:
746-751
(2) Reis-Filho JS, Schmitt FC.. Lymphangiogenesis in tumours: what do
we know? Microsc Res Tech 2003; 60: 171-180.
(3) Padera TP, Stoll BR, Tooderman JB, Capen D, Di Tommaso E, Jain RK.
Cancer cells compress intratumour vessels. Nature 2004; 427: 695.
(4) Williams CSM, Leek RD, Robson AL et al. Absence of
lymphangiogenesis and intratumoral lymph vessels in human metastatic
breast cancer. J Pathol 2003; 200: 195-206.
(5) Jackson DG. The lymphatics revisited. New perspectives from the
hyaluronan receptor LYVE-1. Trens Cardiovasc 2003; 13: 1-7.
(6) Scavelli C, Weber E, Aglianò M et al. Lymphatics at the croosroads
of angiogenesis and lymphangiogenesis. J Anat 2004; 204: 433-449.
(7) Dales JP, Garcia S, Bonnier P, Duffaud F et al. Prognostic
significance of VEGF receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) in
breast carcinoma. Ann Pathol 2003; 23: 297-305.
I read with interest the recent article by Cook et al. and do agree that
examination of breast reduction specimen is beneficial since incidental
malignancy/high risk lesions are well documented.The problem has often
been one of examination of relatively large breast reduction specimens
with attendant time and resource constraints, often requiring random
sampling.
I read with interest the recent article by Cook et al. and do agree that
examination of breast reduction specimen is beneficial since incidental
malignancy/high risk lesions are well documented.The problem has often
been one of examination of relatively large breast reduction specimens
with attendant time and resource constraints, often requiring random
sampling.
Specimen mammography (SM) offers an efficient and potentially less time
consuming method of examining the breast reduction specimen.The use of SM
is currently limited to a few units. A recent survey (in-press) of Plastic
Surgeons of UK and Ireland however revealed that only 5 % of a total of
260 surgeons request SM routinely, 7% occasionally do while 88% never
request SM.[1]
Only one study has addressed the role of mammography in breast
reduction; Ozmen et al in a relatively small case series of forty women
investigated the potential benefits of specimen radiography in detection
of breast pathologies in breast reduction tissue,they found the use of SM
useful specifically in guiding the histopathologist to high risk areas to
examine.[2]
Thus the question of SM is one that needs to be addressed , especially
from a cost-benefit viewpoint.
References
1) Iwuagwu OC, Platt AJ, Drew PJ Reduction Mammoplasty in UK &
Ireland- current trends. In Press BJPS.
2) Ozmen S, Yavuzer R, Latifoglu O, Ayhan S ,Tuncer S ,Yazici I,
Atabay K. Specimen radiography: an assessment method for reduction
mammaplasty materials. Aesth. Plast. Surg. Vol. 25: 432-435,2001.
The paper by Goodson and Vernon on public opinions of tissue sample
use,[1] contains a fundamental flaw which, unless I am mistaken, ought to have
prevented its publication.
It is generally accepted that post mortem tissue has much greater
emotional significance than samples of human tissue removed from living
patients. This is supported by a survey of public opinion conducted by
the MRC a...
The paper by Goodson and Vernon on public opinions of tissue sample
use,[1] contains a fundamental flaw which, unless I am mistaken, ought to have
prevented its publication.
It is generally accepted that post mortem tissue has much greater
emotional significance than samples of human tissue removed from living
patients. This is supported by a survey of public opinion conducted by
the MRC and the Wellcome Trust since the events at Alder Hay were
published.[2] It is also the stated opinion of members of the Retained
Organs Commission. It should be self-evident, if one merely considers how
a lock of hair from a deceased relative may be treasured in a silver
casket, but at the hairdresser the same material is unceremoniously dumped
in the bin.
Furthermore, the emotional significance of whole organs is greater
than that of small groups of cells.
Goodson and Vernon purport throughout their paper to be discussing
research using tissue removed for therapeutic or diagnostic purposes from
living patients.
However, the questionnaire they administered (their figure 1) does
not make this clear; it merely asks about “pieces of any of the following
body tissues or organs”, followed by a list which includes heart and
brain, emotionally important organs which are rarely removed other than at
autopsy.
Nowhere is it explained that the questions should relate to specimens
which have already been removed and which, if not used for the good of
mankind, would otherwise be incinerated.
Nowhere is the size of the “piece” defined, or the reason for its
removal.
If one approaches someone in a dental surgery waiting room and says
“Can I use a piece of your brain for research?” it is hardly surprising
that a high proportion refuse!
The authors mention the striking difference between their results and
others published in the literature. They mention the 99% consent rate
from the Peterborough Tissue Bank, and wrongly ascribe the difference in
their results to changes since Alder Hay. A very recent report from
Peterborough has confirmed that their consent rate remains 99%, even
though the tissue is to be transferred to commercial research companies.[3]
The authors also question whether having surgeons requesting consent
could result in coercion. This too does not apply to the Peterborough
tissue bank, where consent is requested by nurses employed by the tissue
bank.
I suggest that the dramatic difference is actually accounted for by
two factors. First, in Peterborough the tissue bank staff take up to 30
minutes per patient to explain the issues before requesting consent.
Second, in Peterborough the patients already know, before they are
approached by the tissue bank, what tissue is to be removed and why. They
are not discussing a hypothetical “lump of brain”. Therefore there is no
possible confusion between consent to removal of tissue and consent to
research use. Goodson and Vernon did nothing to explain to the dental
patients why tissue might be removed.
This raises a further issue which is ignored by Goodson and Vernon.
One frequently hears the phrase “fully informed consent”. Is there not
such a thing as fully informed refusal?
The ethical importance of adequately informed refusal is self-evident from
the following hypothetical scenario.
Imagine a patient who is asked to consent to research use of resected
tissue without further explanation. The patient refuses, in the mistaken
belief that their consent will remove all safeguards and that their tissue
could then be used for unethical purposes such as reproductive cloning.
Imagine that the patient subsequently has a full explanation and
realises that: (i) their original fears were unfounded and (ii) their own
medical treatment and diagnosis have been based on the use of tissue from
other, previous patients; a benefit which their refusal has now denied to
future patients.
I believe that this could readily induce a sense of shame, guilt and
anger in an altruistic patient who has been misled into inadequately
informed refusal, and who has therefore been deceived.
The enormous importance of all this is obvious when considering the
new Human Tissue Bill. Not only does this Bill absurdly provide almost
identical “protection” for cells in urine samples to that provided to the
hearts and brains of dead babies. It is also being introduced with an
assumption by Ministers that requesting and recording consent for
subsequent tissue use can be done in almost no time at all – certainly
less than a minute. Even if patients are always asked (which seems
unlikely), inadequately informed refusal seems inevitable.
I fear that in the future the results of Goodson and Vernon will be
inappropriately and uncritically cited by those who wish to apply
restrictions on the use of human tissue, as evidence that large
proportions of patients object to research use of their specimens – even
when the ‘tissue’ is a urine sample or a cervical smear. Other, better
studies have already shown that, if adequately informed, the vast majority
of patients consent to the research use of surgically resected tissue,
even if the research is in a commercial setting.[3]
If this happens, your publication of this seriously flawed paper will
have done a disservice to pathologists, to medicine and to the well being
of future patients.
References
1. Goodson M L, Vernon B G. A study of public opinion on the use of tissue
samples from living subjects for clinical research. J Clin Pathol 2004;
57:135-8.
The fear of overwhelming infection following splenectomy has had a
profound and detremental effect upon the recent evolution of surgical
practice. Extraordinary efforts to save the spleen are now the rule
usually in the hands of trainees and inexperienced or inadequately trained
surgeons. The methods include splenic repair, partial splenectomy,
wrapping the spleen in a Dexon mesh, non-operative manageme...
The fear of overwhelming infection following splenectomy has had a
profound and detremental effect upon the recent evolution of surgical
practice. Extraordinary efforts to save the spleen are now the rule
usually in the hands of trainees and inexperienced or inadequately trained
surgeons. The methods include splenic repair, partial splenectomy,
wrapping the spleen in a Dexon mesh, non-operative management, and saving
the spleen in the course of performing a distal pancreatectomy.[1-4]
These can be challenging operations for the most experienced of abdominal
surgeons who as a rule like to avoid all unnecessary risks.
Splenic repair is neither simple nor safe. In one study of 200 adults
who sustained splenic trauma and underwent laparotomy splenorrhaphy was
accomplished in 85 patients (42 percent).[1] Methods of repair in this
study included cautery and hemostatic agents in 24 patients (28 percent),
debridement and suturing in 42 patients (50 percent), and partial
resection in 19 patients (22 percent). Postoperative complications
occurred in 14 patients. Four were intraabdominal. Three patients required
reoperation for splenic hemorrhage; one (2 percent) after suture repair
and two (11 percent) after partial resection. A left subphrenic abscess
developed in another patient. There were 5 deaths.
The evidence base upon which these changes in practice have been
based is not strong. The reality is the risk of overwhelming sepsis after
splenectomy is very small certainly in adults and the development of
pneumococcal septicaemia is not necessarily fatal.[5] What is more there
are other causes for overwhelming sepsis in most of the patients. These
include associated diseases with immunological impairmnt, including
malignancies, and the immunological compromise caused by blood
transfusions and/or accompanying development of shock.[6]
The commonest reason for a splenectomy in adults is incidental injury
(7). The risk of splenic injury is highest during left hemicolectomy (1-
8%), open anti-reflux procedures (3-20%), left nephrectomy (4-13%) and
during exposure and reconstruction of the proximal abdominal aorta and its
branches (21-60%). [Risks of this magnitude are a serious indictment of
the overall standard of surgery being practiced in the UK for
thiscomplication is a rarity in the hands of properly trained and
experienced abdominal surgeons].
Splenic injury results in prolonged operating time, increased blood
loss and longer hospital stay. It is also associated with a two to ten-
fold increase in post operative infection rate and up to a doubling of
morbidity rates. Mortality is also reported to be higher in patients
undergoing splenectomy for iatrogenic injury. [These too are a serious
indictment of the overall standard of surgical practice in the UK].
Two complications of conservative management of splenic injuries are
of particular concern, delayed rupture of the spleen with the development
of haemorrhagic shock in unfavourable circumstances [8,9] and an intra-
abdominal abscess.[10] Both are serious complications that can be
difficult to manage satisfactorily and are often fatal. In earlier days
the development of a subphrenic abscess had an associated mortality as
high as 50%. Should patients develop one the these complicatios the sooner
they are recognised the easier they are to resolve satisfctorily. Anyone
one who has had a splenic salvage operation requires, therefore, careful
follow-up with sequential CT scans, an option that is expensive and not
available in all communities even in developed countries.
The complications of splenic salvage are infrequent. The risk
increases with more complex salvage attempts especially in the hands of
trainees and inadequately trained or inexperienced surgeons. Splenic
reimplantation has been advocated as a safe alternative [1] but is not
without risk and is of unproven benefit in preventing overwhelming sepsis.
Even giving pneumovax [pneumococcal vaccine] is not without risk in the
critically ill and, for this reason, is administered only when a patient
is ready to be discharged. Iatrogenic splenic injuries are invariably the
product of suboptmal technique. Trainees need to be taught how to perform
a splenectomy for a bleeding spleen rapidly, effectively and safely. The
more experience they get the better. The proliferation of splenic salvage
has compromised the opportunity to acquire this experience, an opportunity
that may be further compromised but the restriction in working hours being
imposed upon trainees by the EU.
The claim that splenectomy per se increases the risk of overwhelming
sepsis is an unproven hypothesis. In the absence of proof of this
hypothesis splenectomy should be restored as the treatment of choice for
all significant splenic injuries certainly in adults. I would define
significant injury as any injury that bleeds significantly. These are
circumstances in which delay in controlling the haemorhage can quickly
make matters infinitely worse.
References
1. Moore FA, Moore EE, Moore GE, Millikan JS. Risk of splenic salvage
after trauma. Analysis of 200 adults.
Am J Surg. 1984 Dec;148(6):800-5.
2. Berry MF, Rosato EF, Williams NN. Dexon mesh splenorrhaphy for
intraoperative splenic injuries.
Am Surg. 2003 Feb;69(2):176-80.
3. Jacobs IA, Kelly K, Valenziano C, Pawar J, Jones C. Nonoperative
management of blunt splenic and hepatic trauma in the pediatric
population: significant differences between adult and pediatric surgeons?
Am Surg. 2001 Feb;67(2):149-54.
4. Giulini SM, Portolani N, Bonardelli S, Baiocchi GL, Zampatti M,
Coniglio A, Baronchelli C. Distal pancreatic resection with splenic
preservation for metastasis of renal carcinoma diagnosed 24 years later
from the nephrectomy]
Ann Ital Chir. 2003;74(1):93-6.
5. van ST, Reardon CM, O'Donnell JA, Kirwan WO, Brady MP. "How safe
is splenectomy?".
Ir J Med Sci. 1994 Aug;163(8):374-8.
6. Fiddian-Green RG. Open versus laparoscopy assisted colectomy.
Lancet. 2003 Jan 4;361(9351):74; author reply 75-6.
7. Cassar K, Munro A. Iatrogenic splenic injury.
J R Coll Surg Edinb. 2002 Dec;47(6):731-41
8. Van Stiegmann G, Moore EE Jr, Moore GE. Failure of spleen repair.
J Trauma. 1979 Sep;19(9):698-700.
9. Knudson MM, Maull KI. Nonoperative management of solid organ
injuries. Past, present, and future.
Surg Clin North Am. 1999 Dec;79(6):1357-71.
10. Bufalari A, Giustozzi G, Moggi L. Postoperative intraabdominal
abscesses: percutaneous versus surgical treatment.
Acta Chir Belg. 1996 Sep-Oct;96(5):197-200.
Dear Editor
We read with interest the report on postulated atorvastatin induced lactic acidosis [1]. In our view, the arguments outlined by its authors do not support this hypothesis at all, for the reasons outlined below:
a) The patient clearly had a mixed acid-base disturbance (combined respiratory alkalosis and metabolic acidosis, as evidenced by the normal pH of 7.39 coupled with severe hypocapnia)....
Dear Editor
In his letter of the letter 18th August 2004, Dr Chandler makes some interesting comments on our paper “Increased neutrophil apoptosis in chronic fatigue syndrome” [1]. He states that “a more likely explanation for the group's findings are that CFS patients have a primary psychological disorder with the secondary expected immune dysfunction”. We strongly disagree with this statement.
It is n...
Dear Editor
I welcome the latest research on neutrophil apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite the concerns raised, by hundreds of well educated people, involved with M.E. worldwide, for many years, someone who ha...
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...
Dear Editor
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Dear Editor
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Dear Editor
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Specimen mammography (...
Dear Editor
The paper by Goodson and Vernon on public opinions of tissue sample use,[1] contains a fundamental flaw which, unless I am mistaken, ought to have prevented its publication.
It is generally accepted that post mortem tissue has much greater emotional significance than samples of human tissue removed from living patients. This is supported by a survey of public opinion conducted by the MRC a...
Dear Editor
The fear of overwhelming infection following splenectomy has had a profound and detremental effect upon the recent evolution of surgical practice. Extraordinary efforts to save the spleen are now the rule usually in the hands of trainees and inexperienced or inadequately trained surgeons. The methods include splenic repair, partial splenectomy, wrapping the spleen in a Dexon mesh, non-operative manageme...
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